Alpha-1 (α1) adrenergic receptors (i.e., α1 adrenoceptors) are G-protein coupled transmembrane receptors that mediate various actions of the sympathetic nervous system through the binding of the catecholamines, epinephrine and norepinephrine (NE). Currently, several subtypes of the α1 adrenergic receptors are known to exist for which the genes have been cloned: αA1A (previously known as α1C), α1B and α1D. Recently the existence of a low affinity α1 adrenoceptor for prazosin named α1L, in human prostate has been determined. However, the gene for the α1L adrenergic receptor subtype has yet to be cloned. The α1 adrenoceptor plays a part in the sympathetic maintenance of smooth muscle tone and α1 adrenergic agonists are known to increase muscle tone in the lower urinary tract (Testa, R., Eur.J.Pharmacol., 249, 307-315 (1993). Pharmacological studies resulting in the subdivision of α1, adrenergic receptors have let to the suggestion that development of subtype-selective compounds may allow improved treatment with a lower incidence of side effects.
Urinary incontinence is a condition defined as the involuntary loss of urine. Stress urinary incontinence (SUI) occurs when the internal sphincter does not close completely. The primary symptom is minor leakage from activities, such as coughing, sneezing, laughing, running, lifting, or even standing, that apply pressure to a full bladder. Leakage stops when the activity stops. SUI is most common in women between the ages of 25 and 50, and many regularly exercising women have some degree of SUI.
The present methods to treat SUI include physiotherapy and surgery. Treatment with pharmaceuticals is limited to the use of non-selective adrenergic agonists.
Only a limited number of pharmaceutical agents have been employed, with varying success, to treat stress incontinence.
Phenylpropanolamine, pseudoephedrine and midodrine are considered first-line therapy for mild to moderate stress incontinence (Wein, supra; Lundberg (editor), JAMA, 1989, 261(18), 2685-2690). These agents are believed to work both by direct activation of a, adrenoceptors and indirectly by displacement of endogenous norepinephrine from sympathetic neurons following uptake into the nerve terminal (Andersson and Sjogren, Progress in Neurobiology, 1982, 71-89). Activation of α1 adrenoceptors located on the smooth muscle cells of the proximal urethra and bladder neck (Sourander, Gerontology, 1990, 36, 19-26; Wein, supra) evokes contraction and an increase in urethral closure pressure.
The utility of phenylpropanolamine, pseudoephedrine, and midodrine is limited by a lack of selectivity among the a, adrenoceptor subtypes and by the indirect action of these agents (i.e., activation of α1, α2, and β-adrenoceptors in the central nervous system and periphery). As a result, any desired therapeutic effect of these agents may be accompanied by undesirable side effects, such as an increase in blood pressure. The increase in blood pressure is dose-dependent and therefore limits the ability to achieve therapeutically effective circulating concentrations of these agents (Andersson and Sjogren, supra). Furthermore, in some patients these agents produce insomnia, anxiety and dizziness as a result of their central nervous system stimulant actions (Andersson and Sjogren, supra, Wein, supra).
While some selective α1A agonists have recently been disclosed for the treatment of stress incontinence, there continues to be a need for medicaments that are useful for the treatment of incontinence. A compound having the desired α1A adrenergic agonist profile is desirable.